Our work of the last ten years supported by NINR emphasizes that the cellular and molecular pathophysiology of ischemic brain injury is strongly influenced by gender and by estrogen deficiency. If we are to formulate therapies for stroke survivors of both sexes, it is essential to understand how mechanisms of cell damage are shaped by male and female sex steroids. We have shown that native estrogens (or 17B estradiol administered at physiological levels) reduce stroke sensitivity, i.e. reduce neuronal damage once an ischemic event has occurred. We have focused largely on brain parenchyma and neurons, rather than vascular elements such as endothelia, in our search for estrogen's anti-ischemic actions. We propose to move into new ground by addressing how estradiol (E2) acts within normal vs post-ischemic cerebral blood vessels. We examine the role of estrogen receptor a in E2's acute protection of microcirculatory function (Aim 1) and in fostering longer- term capillary generation de novo (angiogenesis, Aim 2). Furthermore, little is known about loss of androgens in aging men and how the "andropause" affects vascular stroke. This gap has remained curiously unaddressed, despite the fact that male sex is a consistent and known risk factor in clinical stroke. This important issue remains understudied, i.e. if androgens can improve outcome from ischemic injury in the middle-aged male animal by a vascular mechanism (Aim 3) or by direct preservation of DNA-damaged neurons (Aim 4). This proposal employs our well-established animal model of focal cerebral ischemia and standard molecular tools, but in an innovative way. Instead of minimizing gender differences or effect of sex hormones, as we traditionally do in experimental research; the present approach will maximize these factors. Our findings will help to elucidate the mechanisms behind a most fundamental "genetic" aspect of ischemia, biological sex.